Catalytic hydrogenation of nitriles

ABSTRACT

The present invention relates to a novel catalytic hydrogenation of substituted 2-methyl cyanopyridyl derivatives, in particular 3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile [=Py-CN] to substituted 2-ethylaminopyridine derivatives, in particular 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine [=Py-ethanamine] or salts thereof in the presence of metal catalysts, in particular palladium catalysts.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 15/033,987, filed 3 May 2016, which is a 371 National Stageentry of PCT/EP2014/074212, filed 11 Nov. 2014, which claims priority toEP 13193164.4, filed 15 Nov. 2013. The disclosures of the priorityapplications are incorporated in their entirety herein by reference.

BACKGROUND Field of the Invention

The present invention relates to a novel catalytic hydrogenation ofsubstituted 2-methyl cyanopyridyl derivatives, wherein the substitutionis present on the pyridine ring, in particular3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile [=Py-CN] to thecorresponding substituted 2-ethylaminopyridine derivatives, inparticular 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine[=Py-ethanamine] or salts thereof in the presence of metal catalystssuch as in particular palladium catalysts.

Description of Related Art

Substituted 2-methyl cyanopyridyl derivatives, wherein the substitutionis present on the pyridine ring, such as in particular3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile are importantintermediates for the preparation of Fluopyram(N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl)benzamide),a commercially available fungicide, according to formula (Ia) shownbelow

The production of Fluopyram is disclosed in WO-A 2004/16088.

In general the catalytic hydrogenation of nitriles is well known in theliterature and can be carried out with different catalysts under eitheracidic or basic condition (Nishimura in “Handbook of HeterogeneousCatalytic Hydrogenation for Organic Synthesis”, pp. 254-285, John Wileyand Sons, New York, 2001). It is also known that the catalytichydrogenation of nitriles to the desired primary amines is usuallyaccompanied by the formation of significant amounts of secondary andtertiary amines which contaminate the desired primary amine and makesthe isolation very complicated, costly and inefficient and thus notsuitable for being used on an industrial scale.

The catalytic hydrogenation of a substituted 2-methyl cyanopyridylderivative to a substituted 2-ethylaminopyridine derivative according toformula (III) or its corresponding ammonium salt under hydrogen pressurein the presence of a metal catalyst in a protic solvent is described inWO 2004/016088 and EP-A 1674455. WO-A 2004/016088 and EP-A 1 674 455disclose concretely the catalytic reduction of[3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile [Py-CN] into[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine [Py-ethanamine] inthe presence of a palladium catalyst on charcoal in a protic solventbeing acetic acid. The method described in WO-A 2004/016088 and EP-A 1674 455 has the drawback in that the yield of the hydrogenation reactionof [Py-CN] followed by hydrolysis of the N-acetyl intermediate to[Py-ethanamine] is low. Another difficulty with this process is thepotential for catalyst deactivation by the large amount of side productsformed which could amount up to 60% of the end product. Side productsinclude but are not limited to dechlorinated compounds, in particular of2-[5-(trifluoromethyl)pyridin-2-yl]ethanamine. The low selectivity tothe desired product and the formation of different side products makesthe economic isolation of the compound according to formula (III) notacceptable at an industrial scale.

It is known in the prior art to improve the hydrogenation of nitriles tothe corresponding amines in the presence of an acylating agent. Forexample, EP-A 1 674 455 discloses a two step synthesis of substituted2-ethylaminopyridine derivatives comprising the catalytic reduction ofreaction of a 2-methylcyanopyridine derivative in the presence of anacylating agent and of a catalyst, in a solvent, under a hydrogenpressure to provide the respective 2-ethylaminopyridyl derivative.

The catalytic hydrogenation step is performed in the presence of anexcess of four equivalents of acetanhydride (Ac₂O). After hydrolysis ofthe intermediate the desired product was formed with significant amountsof side product. In addition, this method does not disclose any workupprocedure nor recycling process of the expensive palladium catalyst. Inaddition, the reaction mixture contains large amounts of hydrochloricacid and is therefore highly corrosive. The solvent methanol reacts withthe hydrochloric acid forming the gas chlormethane which is toxic andneeds to be separated. Consequently the process described isdisadvantageous from the economic, environmental and safety standpoint.

WO 2004/041210 relates to compounds, which are useful in the treatmentof bacterial infections. Therein, the preparation of a substitutedpyridinyl carbamate is mentioned, comprising the step of reacting asubstituted pyridinyl acetonitrile compound to the correspondingsubstituted pyridinyl amine compound in THF under addition of BH₃.THFand HCl, followed by NaOH addition and extraction with EtOAc. However,therein no presence of a metal catalyst, particularly no palladiumcatalyst, is mentioned.

WO 2008/125839 relates to specific pyrimidine compounds and thepharmaceutical use thereof. Therein, the preparation of2-(6-methyl-pyridin-2-yl) ethanamine from the correspondingpyridine-2-yl acetonitrile in THF under addition of borane dimethylsulfide complex in THF and subsequent addition of HCL is mentioned.However, therein no presence of a metal catalyst, particularly nopalladium catalyst, is mentioned.

WO 2011/047156 relates to small molecule heterocyclic inhibitors ofsepiapterin reductase and the medical use thereof. Therein, the reactionof a chlorine substituted pyridinyl acetonitrile compound to thecorresponding chlorine substituted pyridinyl ethanamine compound in THFunder addition of BH₃.DMS. However, therein neither acid addition northe presence of a metal catalyst, particularly no palladium catalyst, ismentioned.

Skerlj et al. (Journal of Organic Chemistry, Vol. 67, No. 4, 2002, pages1407-1410) relates to the synthesis of azamacrocyles, wherein the ringnitrogens are regioselectively functionalized. Therein, an organozincpalladium catalysed coupling with a functionalized bromopyridine iscarried out. However, therein only a borane reduction followed by aso-called Nehishi coupling but no catalytic hydrogenation is carriedout. In any case, the borane reduction reaction as described therein isnot suitable in large scale production as it makes use and leads toundesired reaction products and is expensive.

None of the described prior art processes is suitable for a large scaleproduction. In contrast, the new process of the present invention, asdescribed in detail hereinafter, provides an economic process withsignificantly reduced formation of unwanted toxic side-products,particularly with reduced formation of unwanted dehalogenatedside-products, and remarkably increased yield of the desired reactionproducts.

The chemoselective catalytic hydrogenation of nitriles according toformula (II) as disclosed below wherein at least one of the Xsubstituents is halogen is in general problematic. Such compounds areeasily dehalogenated during the catalytic hydrogenation thus formingundesired dehalogenated side-products.

A respective 2-methyl cyanopyridyl derivative according to formula (II),wherein at least one X substituent is halogen, preferably chlorine, canbe defined by the following formula (II′) below. Upon dehalogenationduring the catalytic hydrogenation process, the correspondingdehalogenated compounds of formula (II″), as defined below, can beformed.

Halogen substituted compound corresponding dehalogenated compound(preferably chlorine substituted compound) (preferably dechlorinatedcompound)

each substituent X is chosen, independently of each substituent X ischosen, independently of the the others, as being hydrogen, halogen,C₁-C₄ others, as being hydrogen, halogen, C₁-C₄ alkyl or alkyl or C₁-C₄haloalkyl with the proviso that C₁-C₄ haloalkyl with the proviso thatthe at least at least one substituent X is halogen, one halogensubstituent, preferably chlorine preferably chlorine substituent, of thecorresponding compound (II′) is replaced by hydrogen

The tendency of a halogen-containing compound to dehalogenate duringcatalytic hydrogenation is higher for bromine- than forchlorine-containing compounds and higher for two- or more foldsubstituted compounds than for onefold substituted compounds. (cf.Nishimura in “Handbook of Heterogeneous Catalytic Hydrogenation forOrganic Synthesis”, pp. 623-637, John Wiley and Sons, New York, 2001). Alarge number of methods with different additives have been developed toreduce the hydrodehalogenation of aromatic compounds. Most of theseadditives have drawbacks such as low chemoselectivity, undesired sideproducts, costs and toxicity.

SUMMARY

It is therefore an object of the present invention to provide a novel,safer, more economically and environmentally viable process suitable forindustrial scale for preparing substituted 2-ethylaminopyridinederivatives of the formula (III) from substituted 2-methyl cyanopyridylderivatives of the formula (II), as defined below.

The object was achieved according to the present invention by a process(A) for preparing substituted 2-ethylaminopyridine derivatives of theformula (III) and corresponding salts thereof,

wherein p is an integer equal to 1, 2, 3 or 4;

each substituent X is chosen, independently of the others, as beinghalogen, C₁-C₄ alkyl or C₁-C₄ haloalkyl;

characterized in that

in step (A1) a substituted 2-methyl cyanopyridyl derivative according toformula (II)

wherein p is an integer equal to 1, 2, 3 or 4;

each substituent X is chosen, independently of the others, as beinghalogen, C₁-C₄ alkyl or C₁-C₄ haloalkyl;

is hydrogenated in the presence of a metal catalyst, a catalystmodifier, and an acid.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

Process (A) may comprise an additional step (A2) after step (A1),

wherein the solvent of the reaction solution comprising the2-ethylaminopyridine derivative according to formula (III) is removed;

Process (A) may comprise an additional step (A3) after steps (A1) and(A2),

wherein a base is added to the remaining residue of step (A2);

Process (A) may comprise an additional step (A4) after steps (A1), (A2),and (A3),

wherein the organic phase (non-water soluble) is separated from thewater phase;

Process (A) may comprise an additional step (A5) after steps (A1), (A2),(A3), and (A4),

wherein the precipitated product according to formula (III) is isolatedfrom the reaction suspension comprising the 2-ethylaminopyridinederivative according formula (III);

Process (A) may comprise an additional step (A6) after steps (A1), (A2),(A3), (A4) and (A5),

wherein the isolated product according to formula (III) is reacted witha benzoyl halide according to formula (IV)

wherein

Hal is fluorine, chlorine or bromine;

q is an integer equal to 1, 2, 3 or 4;

each substituent Y is chosen, independently of the others, as beinghalogen, C₁-C₄ alkyl or C₁-C₄ haloalkyl;

to the compound according to formula (I)

wherein p and X are defined as above;

q is an integer equal to 1, 2, 3 or 4;

each substituent Y is chosen, independently of the others, as beinghalogen, C₁-C₄ alkyl or C₁-C₄ haloalkyl.

Optionally in step (A1) and (A3) a solvent can be added.

Optionally in step (A4) acid can be added to the organic phase.

Optionally in step (A4) remaining water can be removed.

Optionally in step (A5) the reaction suspension is taken up with afurther amount of solvent.

p is preferably 1 or 2.

p is very preferably 2.

In each case, X is preferably independently of the others, as beingfluorine, chlorine, bromine, C₁-C₂ alkyl or C₁-C₂ haloalkyl having 1 to5 halogen atoms selected independently from each other from fluorine,chlorine;

In each case, X is more preferably independently of the others, as beingfluorine, chlorine, methyl, ethyl or C₁-C₂ haloalkyl having 1 to 5halogen atoms selected independently from each other from fluorine,chlorine;

In each case, X is particular preferably independently of the others, asbeing fluorine, chlorine, or difluoromethyl, trifluoromethyl,dichloromethyl, trichloromethyl;

In each case, X is very particular preferably independently of theothers, as being chlorine, or trifluoromethyl.

As regards the positions in which the 2-pyridyl moiety is substituted byX, the 2-pyridyl moiety is preferably substituted by X in 3- and/or in5-position. Preferably, the 2-pyridyl moiety is substituted by X in 3-and 5-position.

q is preferably 1 or 2.

q is very preferably 1.

Y is preferably independently of the others, as being fluorine,chlorine, bromine, C₁-C₂ alkyl or C₁-C₂ haloalkyl having 1 to 5 halogenatoms selected independently from each other from fluorine, chlorine;

Y is more preferably independently of the others, as being fluorine,chlorine, methyl, ethyl or C₁-C₂ haloalkyl having 1 to 5 halogen atomsselected independently from each other from fluorine, chlorine;

Y is particular preferably independently of the others, as beingfluorine, chlorine, or difluoromethyl, trifluoromethyl, dichloromethyl,trichloromethyl;

Y is very particular preferably trifluoromethyl.

Y is very particular preferably chlorine.

As regards the positions in which the phenyl moiety is substituted by Y,the phenyl moiety is preferably substituted by Y in 2- and/or in6-position. Preferably, the phenyl moiety is substituted by Y in2-position.

Very particular preferably the compound according to formula (II) is3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile and the compoundaccording to formula (III) is2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine. Very preferablythe compound according to formula (IV) is 2-trifluoromethyl-benzoylchloride.

Very preferably the compound according to formula (I) is fluopyram asdefined in formula (Ia).

The corresponding salts of the compounds according to formula (I) arepreferably hydrogensulfates, sulfates, hydrochlorides, phosphates,formates, or acetates.

Preferably step (A6) is performed in the presence of a base.

Useful bases which may be used in the process according to the presentinvention, such as in particular in step (A3) and/or (A6) are inorganicor organic bases such as Na₂CO₃, NaHCO₃, K₂CO₃, KHCO₃, NaOH, KOH,Ca(OH)₂, Mg(OH)₂, triethyl amine, N,N-diisopropylethylamine.

The following bases are particularly preferred for step (A3): Na₂CO₃,NaHCO₃, K₂CO₃, KHCO₃, NaOH, KOH, Ca(OH)₂. More preferred are NaOH, KOH,Ca(OH)₂. Mostly preferred are NaOH, KOH. Preferably, in step (A3) a baseas defined herein is added until adjustment of the pH value of thereaction solution to pH 4 to 14, preferably pH 6 to 13 is achieved.

The following bases are particularly preferred for step (A6): Na₂CO₃,NaHCO₃, K₂CO₃, KHCO₃, NaOH, KOH, Ca(OH)₂. More preferred are NaOH, KOH,Ca(OH)₂. Mostly preferred are NaOH, KOH. Preferably, in step (A6) a baseas defined herein is added until adjustment of the pH value of thereaction solution to pH 4 to 14, preferably pH 6 to 13 is achieved.

The corresponding salts of the compounds according to formula (III) arepreferably hydrogen sulfates, sulfates, hydrochlorides, dihydrogenephosphates, hydrogen phosphates, phosphates, mesylates, citrates,formates, or acetates.

The metal catalyst is any hydrogenation catalyst selected from the groupof palladium, platinum, ruthenium, and rhodium catalysts. In oneembodiment the metal catalyst is any hydrogenation catalyst selectedfrom the group of palladium, platinum, and ruthenium catalysts.

In one embodiment the metal catalyst is any hydrogenation catalystselected from the group of palladium, platinum, and rhodium catalysts.Palladium (Pd), platinum (Pt) or a combination thereof as catalysts arepreferred catalytically active metal catalysts. Palladium (Pd), platinum(Pt) or a combination thereof or Rhodium catalysts are preferredcatalytically active metal catalysts. Particularly preferred arepalladium catalysts. Even more preferred are palladium catalysts fromthe group consisting of elemental palladium and palladium compoundswhich are reducible by hydrogen or any other reducing agents (e.g.sodium formate, hydrazine) to elemental palladium at the hydrogenationconditions as applied in the process of the present invention, andmixtures thereof.

The metal catalysts may be present in any chemical form, for example inelemental, colloidal, salt or hydroxide, oxide form, together withcomplexing agents as chelates. The metal catalysts may be present insupported form, i.e. applied to any support, preferably an organic orinorganic support. Examples of suitable supports are carbon (charcoal oractivated carbon), aluminium oxide, silicon dioxide, zirconium dioxide,titanium dioxide, calcium carbonate, barium sulphate and zeolite.Preferred supports are carbon such as charcoal and activated carbon.

The metal loading on such a support is between 0.01% and 100%, morepreferably in the range of 0.5% to 50% and even more preferably in therange of 0.5% to 25%, and most preferably in the range of 1% to 20% andbetween 5% and 20%. Further preferred ranges further include a metalloading on such support between 0.5% and 10%, between 0.5% and 20%,between 1% and 10%, between 1% and 5%, between 1% and 3%, between 3% and10%, between 3% and 20%, and between 5% and 10%.

Preferred catalysts in supported form are selected from palladium andplatinum catalysts, with palladium catalysts in supported form beingparticularly preferred.

Therefrom, preferred catalysts, which are present in supported form, arePd/C, Pd(OH)₂/C, Palladium oxide/C, mixed Palladium oxide-hydroxide/C,Palladium oxide/Al₂O₃, mixed Palladium oxide-hydroxide/Al₂O₃, Palladiumoxide/SiO₂, mixed Palladium oxide-hydroxide/SiO₂, Pd/CaCO₃,Pd/C-diphenylsulfide, Pd/Al₂O₃, Pd/SiO₂, Pd/BaSO₄,Pd(II)acetate-Polymethylhydrosiloxane, Pd (Fe)/C, Pd/C 5% sulfur, Pt/C,Pt/C-5% sulfur, Pt/Al₂O₃.

Further suitable catalysts are Pd/V catalysts such as 5% Pd/0.5% V,Pd/Pt catalysts such as 4% Pd/1% Pt.

Particularly preferred catalysts, which are present in supported form,are Pd/C, Pd/Al₂O₃, Pd(OH)₂/C, Palladium oxide/C, mixed Palladiumoxide-hydroxide/C, Palladium oxide/Al₂O₃, mixed Palladiumoxide-hydroxide/Al₂O₃, Palladium oxide/SiO₂, mixed Palladiumoxide-hydroxide/SiO₂, Pd/SiO₂.

Very particularly preferred catalysts are Pd/C, Pd/Al₂O₃, Pd(OH)₂/C,Palladium oxide/C, mixed Palladium oxide-hydroxide/C, Palladiumoxide/Al₂O₃, mixed Palladium oxide-hydroxide/Al₂O₃, Palladiumoxide/SiO₂, mixed Palladium oxide-hydroxide/SiO₂, Pd/SiO₂ having a metalloading in the range of 0.5% to 25%, preferably in the range of 0.5% to25%, more preferably in the range of 1% to 20%, even more preferably inthe range of 3 to 20%, most preferably in the range of 5 to 20%.

Very particularly preferred catalysts are

1% to 25%, preferably 2% to 20%, preferably 3% to 20%, preferably 5% to20% Pd/C,

1% to 25%, preferably 2% to 20%, preferably 3% to 20%, preferably 5% to20% Pd/Al₂O₃,

1% to 25%, preferably 2% to 20%, preferably 3% to 20%, preferably 5% to20% Pd(OH)₂/C,

1% to 25%, preferably 2% to 20%, preferably 3% to 20%, preferably 5% to20% Palladium oxide/C,

1% to 25%, preferably 2% to 20%, preferably 3% to 20%, preferably 5% to20% mixed Palladium oxide-hydroxide/C,

1% to 25%, preferably 2% to 20%, preferably 3% to 20%, preferably 5% to20% Palladium oxide/Al₂O₃,

1% to 25%, preferably 2% to 20%, preferably 3% to 20%, preferably 5% to20% mixed Palladium oxide-hydroxide/Al₂O₃,

1% to 25%, preferably 2% to 20%, preferably 3% to 20%, preferably 5% to20% Palladium oxide/SiO₂,

1% to 25%, preferably 2% to 20%, preferably 3% to 20%, preferably 5% to20% mixed Palladium oxide-hydroxide/SiO₂,

1% to 25%, preferably 2% to 20%, preferably 3% to 20%, preferably 5% to20% Pd/SiO₂.

Very particularly preferred catalysts are 1% Pd/C, 1% Pd/Al₂O₃, 1%Pd(OH)₂/C, 1% Palladium oxide/C, 1% mixed Palladium oxide-hydroxide/C,1% Palladium oxide/Al₂O₃, 1% mixed Palladium oxide-hydroxide/Al₂O₃, 1%Palladium oxide/SiO₂, 1% mixed Palladium oxide-hydroxide/SiO₂, 1%Pd/SiO₂.

Very particularly preferred catalysts are 2% Pd/C, 2% Pd/Al₂O₃, 2%Pd(OH)_(2/)C, 2% Palladium oxide/C, 2% mixed Palladiumoxide-hydroxide/C, 2% Palladium oxide/Al₂O₃, 2% mixed Palladiumoxide-hydroxide/Al₂O₃, 2% Palladium oxide/SiO₂, 2% mixed Palladiumoxide-hydroxide/SiO₂, 2% Pd/SiO₂.

Very particularly preferred catalysts are 3% Pd/C, 3% Pd/Al₂O₃, 3%Pd(OH)_(2/)C, 3% Palladium oxide/C, 3% mixed Palladiumoxide-hydroxide/C, 3% Palladium oxide/Al₂O₃, 3% mixed Palladiumoxide-hydroxide/Al₂O₃, 3% Palladium oxide/SiO₂, 3% mixed Palladiumoxide-hydroxide/SiO₂, 3% Pd/SiO₂.

Very particularly preferred catalysts are 4% Pd/C, 4% Pd/Al₂O₃, 4%Pd(OH)₂/C, 4% Palladium oxide/C, 4% mixed Palladium oxide-hydroxide/C,4% Palladium oxide/Al₂O₃, 4% mixed Palladium oxide-hydroxide/Al₂O₃, 4%Palladium oxide/SiO₂, 4% mixed Palladium oxide-hydroxide/SiO₂, 4%Pd/SiO₂.

Very particularly preferred catalysts are 5% Pd/C, 5% Pd/Al₂O₃, 5%Pd(OH)_(2/)C, 5% Palladium oxide/C, 5% mixed Palladiumoxide-hydroxide/C, 5% Palladium oxide/Al₂O₃, 5% mixed Palladiumoxide-hydroxide/Al₂O₃, 5% Palladium oxide/SiO₂, 5% mixed Palladiumoxide-hydroxide/SiO₂, 5% Pd/SiO₂.

Very particularly preferred catalysts are 7% Pd/C, 7% Pd/Al₂O₃, 7%Pd(OH)₂/C, 7% Palladium oxide/C, 7% mixed Palladium oxide-hydroxide/C,7% Palladium oxide/Al₂O₃, 7% mixed Palladium oxide-hydroxide/Al₂O₃, 7%Palladium oxide/SiO₂, 7% mixed Palladium oxide-hydroxide/SiO₂, 7%Pd/SiO₂.

Very particularly preferred catalysts are 10% Pd/C, 10% Pd/Al₂O₃, 10%Pd(OH)_(2/)C, 10% Palladium oxide/C, 10% mixed Palladiumoxide-hydroxide/C, 10% Palladium oxide/Al₂O₃, 10% mixed Palladiumoxide-hydroxide/Al₂O₃, 10% Palladium oxide/SiO₂, 10% mixed Palladiumoxide-hydroxide/SiO₂, 10% Pd/SiO₂.

Very particularly preferred catalysts are 15% Pd/C, 15% Pd/Al₂O₃, 15%Pd(OH)_(2/)C, 15% Palladium oxide/C, 15% mixed Palladiumoxide-hydroxide/C, 15% Palladium oxide/Al₂O₃, 15% mixed Palladiumoxide-hydroxide/Al₂O₃, 15% Palladium oxide/SiO₂, 15% mixed Palladiumoxide-hydroxide/SiO₂, 15% Pd/SiO₂.

Very particularly preferred catalysts are 20% Pd/C, 20% Pd/Al₂O₃, 20%Pd(OH)_(2/)C, 20% Palladium oxide/C, 20% mixed Palladiumoxide-hydroxide/C, 20% Palladium oxide/Al₂O₃, 20% mixed Palladiumoxide-hydroxide/Al₂O₃, 20% Palladium oxide/SiO₂, 20% mixed Palladiumoxide-hydroxide/SiO₂, 20% Pd/SiO₂.

Very particularly preferred catalysts are 25% Pd/C, 25% Pd/Al₂O₃, 25%Pd(OH)_(2/)C, 25% Palladium oxide/C, 25% mixed Palladiumoxide-hydroxide/C, 25% Palladium oxide/Al₂O₃, 25% mixed Palladiumoxide-hydroxide/Al₂O₃, 25% Palladium oxide/SiO₂, 25% mixed Palladiumoxide-hydroxide/SiO₂, 25% Pd/SiO₂.

The catalysts are available from commercial sources like the companiesBASF, Acros, Evonik.

The catalysts can be used in any form, for example dry, or wet(water-wet). Preferably, the catalysts are used several times. Morepreferably, the catalysts are used more than two times. Most preferably,the catalysts are used between two times and 10 times. The catalysts canbe used in in a batch, semibatch or fixed bed hydrogenation reaction aswell as in a continuous hydrogenation reaction process. More preferablythe catalysts can be used in in a batch or fixed bed hydrogenationreaction.

In the process according to the invention, the catalyst is used in aconcentration of about 0.01 mol % to about 50 mol % catalyst withrespect to the amount of cyanopyridyl derivative according to formula(II). The catalyst is preferably used in a concentration of about 0.1 toabout 50 mol %, more preferably the catalyst is used in a concentrationof about 0.5 mol % to about 3 mol %.

Catalyst modifiers are such compounds which are capable of modifying theactivity of the catalyst in such a way that the dehalogenation, inparticular the dechlorination, of a halogen substituted, particularlychlorine substituted, 2-methyl cyanopyridyl derivative according toformula (II) and (II′), as defined above, by forming the dehalogenated,particularly dechlorinated, corresponding compound of formula (II″), asdefined above, is reduced compared to the reaction without the catalystmodifier. Whilst not being bound by theory, in the process of thepresent invention the modifier influences, in particular attenuates theactivity of the metal catalyst, in particular of the palladium catalystsand thus reduces the formation of the unwanted dehalogenated,particularly the dechlorinated, side-products. One the one hand, thisreduces the toxicity and on the other hand enhances the yield of thedesired reaction products.

By using the catalyst modifier in the process of the present invention areduction of the dehalogenated, particularly dechlorinated,side-products is achieved, preferably to equal or less than 25%, morepreferably equal or less than 20%, even more preferably equal or lessthan 15%, particular more preferably equal or less than 10%, evenparticular more preferably equal or less than 5%, most preferably equalor less than 3%, most particular preferably equal or less than 1%, canbe achieved. It is in particular possible to reduce the amount ofdehalogenated, particularly dechlorinated, side-products by a factor ofat least 6, preferably of at least 10, more preferably of at least 30compared to the respective reaction without using the modifier.

Suitable catalyst modifiers are organic or inorganic sulfur-containingcompounds such as thiophene, tetrahydrothiophene, 2-mercaptophenol,cysteine, 3,6-dithia 1,8 octadiol, 2,2′-thiobisethanol, diphenylsulfide, thiophenol, thioanisole, sulfolane, thiourea, Na₂S₂O₃-xH₂O,Na₂S, amines such as alkylamines, benzylamines, pyridines, morpholines,polyamines, amidines (e.g. chinoline); a inorganic or organic compoundscomprising phosphor e.g. PPh₃; molybdenum containing compounds e.g.Mo(CO)₆ Vanadium oxides or sulfides e.g. V(V) oxide, V(IV) oxide, V(III)sulfide, NH₄VO₃; Lewis acids (e.g. ZnBr₂, ZnCl₂, MgBr₂, MgO, saltscomprising Fe e.g. FeCl₂, FeCl₃, Fe(OAc)₂); tetraalkylammonium salts(e.g. iodides, bromides and chlorides) such as n-tetramethylammoniumiodide, n-tetraethylammonium iodide, n-tetrabutylammonium iodide,n-tetramethylammonium bromide (TMAB), n-tetraethylammonium bromide,n-tetrabutylammoniumbromide (TBAB), n-tetramethylammonium chloride,n-tetraethylammonium chloride, n-tetrabutylammoniumchloride; inorganicsalts such as halides (e.g. NaCl, NaBr, NaI, KCl, KBr, KI, LiBr) orMgBr₂, AlCl₃, CeCl₃, CuCl, CuBr, CuI, CuBr₂,

Suitable catalyst modifiers are organic or inorganic sulfur-containingcompounds such as thiophene, tetrahydrothiophene, 2-mercaptophenol,cysteine, 3,6-dithia 1,8 octadiol, 2,2′-thiobisethanol, diphenylsulfide, thiophenol, thioanisole, sulfolane, thiourea, Na₂S₂O₃-xH₂O,Na₂S; amines such chinoline, inorganic or organic compound comprisingphosphor e.g. PPh₃; molybdenum containing compounds e.g. Mo(CO)₆,Vanadium oxides or sulfides e.g. V(V) oxide, V(IV) oxide, V(III)sulfide, NH₄VO₃; Lewis acids (e g ZnBr₂, ZnCl₂, MgBr₂, MgO, saltscomprising Fe e. g. FeCl₂, FeCl₃, Fe(OAc)₂); tetraalkylammonium salts(e.g. iodides, bromides and chlorides) such as n-tetramethylammoniumiodide, n-tetraethylammonium iodide, n-tetrabutylammonium iodide,n-tetramethylammonium bromide (TMAB), n-tetraethylammonium bromide,n-tetrabutylammoniumbromide (TBAB), n-tetramethylammonium chloride,n-tetraethylammonium chloride, n-tetrabutylammoniumchloride; inorganicsalts such as halides (e. g. NaCl, NaBr, NaI, KCl, KBr KI, LiBr,) orMgBr₂, AlCl₃, CeCl₃, CuCl, CuBr, CuI, CuBr₂.

Suitable catalyst modifiers being organic sulfur-containing compoundsare selected from the group consisting of thiophene,tetrahydrothiophene, 2-mercaptophenol, cysteine, 3,6-dithia 1,8octadiol, 2,2′-thiobisethanol, diphenyl sulfide, thiophenol,thioanisole, sulfolane, thiourea, Na₂S₂O₃-xH₂O, Na₂S.

Preferred suitable catalyst modifiers being organic sulfur-containingcompounds are selected from the group consisting of,tetrahydrothiophene, 2-mercaptophenol, cysteine, 3,6-dithia 1,8octadiol, thiourea.

Preferred suitable catalyst modifiers being inorganic or organiccompounds comprising phosphor are selected from the group consisting ofPPh₃.

Preferred suitable catalyst modifiers being molybdenum containingcompounds are selected from the group consisting of Mo(CO)₆

Preferred suitable catalyst modifiers being Vanadium oxides or sulfidesare selected from the group consisting of V(V) oxide, V(IV) oxide,V(III) sulfide, NH₄VO₃.

Suitable catalyst modifiers being Lewis acids are selected from thegroup consisting of ZnBr₂, ZnCl₂, MgBr₂, MgO, Fe, FeCl₂, FeCl₃,Fe(OAc)₂.

Preferred suitable catalyst modifiers being Lewis acids are selectedfrom the group consisting of ZnBr₂, FeCl₃, Fe(OAc)₂.

Suitable catalyst modifiers being tetraalkylammonium salts are selectedfrom the group consisting of tetramethylammonium iodide,n-tetraethylammonium iodide, n-tetrabutylammonium iodide,n-tetramethylammonium bromide (TMAB), n-tetraethylammonium bromide,n-tetrabutylammoniumbromide (TBAB), n-tetramethylammonium chloride,n-tetraethylammonium chloride, n-tetrabutylammoniumchloride.

Preferred suitable catalyst modifiers being tetraalkylammonium salts areselected from the group consisting of n-tetramethylammonium bromide(TMAB), n-tetrabutylammoniumbromide (TBAB).

Suitable catalyst modifiers being inorganic salts are selected from thegroup consisting of NaCl, NaBr, NaI, KCl, KBr, KI, LiBr, MgBr₂, AlCl₃,CeCl₃, CuCl, CuBr, CuI, CuBr₂.

Preferred suitable catalyst modifiers being inorganic salts are selectedfrom the group consisting of NaBr, NaI, KBr, KI, CuI.

Suitable catalyst modifies being amines are alkylamines, benzylamines,pyridines, morpholines, polyamines, amidines (e.g. chinoline).

A preferred suitable catalyst modifier being amines is chinoline.

More preferred catalyst modifiers are selected from

a) being organic sulfur-containing compounds selected from the groupconsisting of thiophene, tetrahydrothiophene, 2-mercaptophenol,cysteine, 3,6-dithia 1,8 octadiol, 2,2′-thiobisethanol, diphenylsulfide, thiophenol, thioanisole, sulfolane, thiourea, Na₂S₂O₃-xH₂O,Na₂S;

b) being Vanadium oxides or sulfides selected from the group consistingof V(V) oxide, V(IV) oxide, V(III) sulfide, NH₄VO₃;

c) being inorganic or organic compounds comprising phosphor are selectedfrom the group consisting of PPh₃;

d) being Lewis acids selected from the group consisting of ZnBr₂, ZnCl₂,MgBr₂, MgO, FeCl₂, FeCl₃, Fe(OAc)₂.

e) being tetraalkylammonium salts selected from the group consisting oftetramethylammonium iodide, n-tetraethylammonium iodide,n-tetrabutylammonium iodide, n-tetramethylammonium bromide (TMAB),n-tetraethylammonium bromide, n-tetrabutylammoniumbromide (TBAB),n-tetramethylammonium chloride, n-tetraethylammonium chloride,n-tetrabutylammoniumchloride.

f) being inorganic salts selected from the group consisting of NaCl,NaBr, NaI, KCl, KBr, KI, LiBr, MgBr₂, AlCl₃, CeCl₃, CuCl, CuBr, CuI,CuBr₂,

g) being molybdenum containing compounds selected from the groupconsisting of Mo(CO)₆,

h) being amines selected from the group consisting of chinoline.

Even more preferred catalyst modifiers are selected from

a) being organic sulfur-containing compounds selected from the groupconsisting of tetrahydrothiophene, 2-mercaptophenol, cysteine,3,6-dithia 1,8 octadiol, thiourea, Na₂S₂O₃-xH₂O, Na₂S;

b) being Vanadium oxides or sulfides selected from the group consistingof V(V) oxide, V(IV) oxide, V(III) sulfide, NH₄VO₃;

c) being inorganic or organic compound comprising phosphor are selectedfrom the group consisting of PPh₃,

d) being Lewis acids selected from the group consisting of ZnBr₂, MgO,FeCl₃, Fe(OAc)₂;

e) being tetraalkylammonium salts selected from the group consisting ofof n-tetramethylammonium bromide (TMAB), n-tetrabutylammoniumbromide(TBAB);

f) being inorganic salts selected from the group consisting of NaBr,NaI, KBr, KI, CuI,

g) being molybdenum containing compounds are selected from the groupconsisting of Mo(CO)₆,

h) being amines selected from the group consisting of chinoline.

Preferred catalyst modifiers are sulfur-containing compounds,tetraalkylammonium halides, alkali halides and other metal halides.Further preferred catalyst modifiers are halide containing compounds,particularly such as selected from the halide containing catalystmodifier compounds as defined above. It is further preferred that thecatalyst modifiers are selected from the group of aprotic compounds,i.e. from the compounds as listed herein, which cannot donate hydrogen.

More preferred catalyst modifiers are 3,6-dithia-1,8-octadiole, CuI,FeBr₃, FeCl₃, Fe(OAc)₂, KI, KBr, MgBr₂, MgO, NaBr, NaI, NH₄VO₃,chinoline, n-tetramethylammonium iodide, n-tetraethylammonium iodide,n-tetrabutylammonium iodide, n-tetramethylammonium bromide (TMAB),n-tetraethylammonium bromide, n-tetrabutylammoniumbromide (TBAB),n-tetramethylammonium chloride, n-tetraethylammonium chloride,n-tetrabutylammoniumchloride, tetrahydrothiophene, thioethanole, thiourea, V(V) oxide, V(IV) oxide, (V(III) sulfide, ZnBr₂.

Even preferred catalyst modifiers are 3,6-dithia-1,8-octadiole, CuI,FeBr₃, FeCl₃, Fe(OAc)₂, KI, KBr, MgBr₂, MgO, NaBr, NaI, NH₄VO₃,chinoline, n-tetramethylammonium bromide, n-tetraethylammonium bromide,n-tetrabutylammoniumbromide, tetrahydrothiophene, thioethanole, thiourea, V(V) oxide, V(IV) oxide, (V(III) sulfide, ZnBr₂. Even preferredmodifiers are 3,6-dithia-1,8-octadiole, FeBr₃, FeCl₃, Fe(OAc)₂, KBr,MgBr₂, MgO, NaBr, NH₄VO₃, chinoline, n-tetramethylammonium bromide,n-tetraethylammonium bromide, n-tetrabutylammoniumbromide,tetrahydrothiophene, thioethanole, V(V) oxide, V(IV) oxide, ZnBr₂.

In one embodiment suitable modifiers are organic sulfur-containingcompounds (e.g. thiophene, tetrahydrothiophene, 2,2′-thiobisethanol,diphenyl sulfide, thiophenol, thioanisole, sulfolane, thio urea, MgO,amines such as alkylamines, benzylamines, pyridines, morpholines,polyamines, amidines, phosphorous acids and its derivatives, metal ionsand salts, or a combination of inorganic/organic phosphorous with avanadium or molybdenum compound, Vanadium oxides or sulfides, NH₄VO₃,Lewis acids (e g ZnBr₂, ZnCl₂, MgBr₂, Fe or salts e. g. FeCl₂, FeCl₃,Fe(OAc)₂), tetraalkylammonium salts (e.g. iodides, bromides andchlorides) inorganic salts such as alkali halides (e. g. NaCl, NaBr,NaI, KCl, KBr KI, LiBr,) or MgBr₂, AlCl₃, CeCl₃, CuCl, CuBr, CuI, CuBr₂.

In another embodiment modifiers are sulfur-containing compounds,tetraalkylammonium halides, alkali halides and other metal halides

In another embodiment modifiers are 3,6-dithia-1,8-octadiole, CuI,FeBr₃, FeCl₃, Fe(OAc)₂, KI, KBr, MgBr₂, MgO, NaBr, NaI, NH₄VO₃,n-tetramethylammonium iodide, n-tetraethylammonium iodide,n-tetrabutylammonium iodide, n-tetramethylammonium bromide,n-tetraethylammonium bromide, n-tetrabutylammoniumbromide,n-tetramethylammonium chloride, n-tetraethylammonium chloride,n-tetrabutylammoniumchloride, tetrahydrothiophene, thioethanole, thiourea, V(V) oxide, V(IV) oxide, (V(III) sulfide, ZnBr₂.

In another embodiment modifiers are 3,6-dithia-1,8-octadiole, CuI,FeBr₃, FeCl₃, Fe(OAc)₂, KI, KBr, MgBr₂, MgO, NaBr, NaI, NH₄VO₃,n-tetramethylammonium bromide, n-tetraethylammonium bromide,n-tetrabutylammoniumbromide, tetrahydrothiophene, thioethanole, thiourea, V(V) oxide, V(IV) oxide, (V(III) sulfide, ZnBr₂. Even preferredmodifiers are 3,6-dithia-1,8-octadiole, FeBr₃, FeCl₃, Fe(OAc)₂, KBr,MgBr₂, MgO, NaBr, NH₄VO₃, n-tetramethylammonium bromide,n-tetraethylammonium bromide, n-tetrabutylammoniumbromide,tetrahydrothiophene, thioethanole, V(V) oxide, V(IV) oxide, ZnBr₂.

In one embodiment the preferred concentrations of the modifiers are inthe range from about 0.0000001 equivalents to about 10 equivalents withrespect to the amount of cyanopyridyl derivative according to formula(II) used in the reaction, more preferably in the range of 0.001equivalents to 2 equivalents and most preferably in the range of 0.01equivalents to 0.1 equivalents.

In a further preferred embodiment of the invention from the definitionof the catalyst modifier organic and inorganic acids are excluded.Therein, in particular, organic acids are excluded, more particularlyacetic acid and sulfuric acid as well as sulfurous acid are excluded. Itis even more preferred, that acetic acid is excluded from the definitionof catalyst modifiers according to the present invention.

Further it is preferred that from the aforesaid preferred group ofcatalyst modifiers comprising sulfur-containing compounds,tetraalkylammonium halides, alkali halides and other metal halidesorganic and inorganic acids, particularly sulfur-containing acids areexcluded.

In a further preferred embodiment of the present invention, a catalystmodifier is used, with organic and/or inorganic acids and/or one or moreof the compounds of the group consisting of CuI, NaI, KI, thio urea andand V(III) sulphide being excluded.

The preferred concentrations of the catalyst modifiers are in the rangefrom about 0.0000001 equivalents to about 10 equivalents with respect tothe amount of cyanopyridyl derivative according to formula (II) used inthe reaction, more preferably in the range of 0.0001 equivalents to 2equivalents and most preferably in the range of 0.0001 equivalents to0.1 equivalents.

Whilst not being bound by theory, in the process of the presentinvention the acid is used to mask and thus protect the catalyst, inparticular the palladium catalysts. During the hydrogenation reactionfree amine compounds are formed which act as a catalyst poison andnearly immediately disable and inactivate the catalyst, thussignificantly reducing the yield of the desired reaction products. Byusing an acid in the hydrogenation process of the present invention,higher recycling rates of the catalysts are possible, which furtherenhances the yield and an economic process management.

Suitable acids to be used in the hydrogenation reaction according to theinvention are proton donating compounds. Preferred are organic acidssuch as acetic acid (CH₃CO₂H), trifluoro acetic acid (CF₃CO₂H), citricacid, p-toluenesulfonic acid, methanesulfonic acid,trifluoromethanesulfonic acid, formic acid or inorganic acids such assulfuric acid (H₂SO₄), phosphoric acid (H₃PO₄) and hydrochloric acid(HCl). Hydrochloric acid may be used in the form of aqueous and/orgaseous hydrochloric acid.

Preferred acids for the hydrogenation reaction of step (A1) are selectedfrom group consisting of acetic acid (CH₃CO₂H), methanesulfonic acid,(aqueous and/or gaseous) HCl and H₂SO₄.

More preferred acids for the hydrogenation reaction of step (A1) areselected from group consisting of acetic acid (CH₃CO₂H), (aqueous and/orgaseous) HCl and H₂SO₄.

More preferred acids for the hydrogenation reaction are selected fromgroup consisting of methanesulfonic acid, (aqueous and/or gaseous) HCland H₂SO₄.

More preferred acids for the hydrogenation reaction are selected fromgroup consisting of acetic acid (CH₃CO₂H), (aqueous and/or gaseous) HCland H₂SO₄.

Mostly preferred acids for the hydrogenation reaction are selected fromgroup consisting of (aqueous and/or gaseous) HCl and H₂SO₄.

It is preferred to use the organic or inorganic acids as an additive inthe hydrogenation reaction according to the invention in concentrationsof the acids in the range from about 0.1 equivalents to about 100equivalents with respect to the amount of cyanopyridyl derivativeaccording to formula (II) used in the reaction, more preferably in therange of 2 equivalents to about 10 equivalents and most preferably inthe range of 0.5 equivalents to 2 equivalents.

In the additional steps following the hydrogenation reaction of step(A1) acids can be added, too. In particular, in step (A4) optionally anacid can be added to the organic phase. Therein, the acids as definedabove can be used, either alone or in mixtures thereof. Preferably, instep (A4) HCl or H₂SO₄ is used, either in aqueous and/or gaseous form.Therein, it is preferred to add the acid in concentrations in the rangeof 0.1 equivalents to about 100 equivalents, more preferably in therange of 0.2 equivalents to about 10 equivalents, most preferably in therange of 0.5 equivalents to about 5 equivalents.

The hydrogenation reaction can be conducted at any suitable reactionconditions. In general the hydrogenation reaction will be conductedunder batch, semi/batch or fixed bed conditions as well as in acontinuous hydrogenation reaction process.

In one embodiment the hydrogenation reaction will be conducted underbatch or fixed bed conditions.

Therein, the hydrogenation reaction is performed in either batch,semi-batch or continuous slurry reactors. Semi-batch hydrogenationinvolves the feeding of the nitrile (with or without acid and with orwithout modifier) to a slurry of catalyst in a solvent (or without). Inthis mode the ratio of nitrile to the catalyst is lower compared tobatch process. In contrast to the batch or semi-batch process in thecontinuous mode the product is removed at the same rate as nitrile as isadded.

According to the present invention the following combinations ofcatalyst, modifier and acid may be used:

TABLE 1 Ref. Catalyst Ref. Modifier Ref. Acid c1 Pd m1 Thiophene a1Sulfuric acid c2 Pd/C m2 Tetrahydrothiophene a2 HCl c3 Pd(OH)₂/C m32-Mercaptophenol a3 Phosphoric acid c4 Pd/Al₂O₃ m4 Cysteine a4Methanesulfonic acid c5 Palladium oxide/C m5 3,6-Dithia 1,8 octadiol c6mixed Palladium oxide-hydroxide/C m6 2,2′-Thiobisethanol c7 Palladiumoxide/Al₂O₃ m7 Diphenyl sulfide c8 mixed Palladium oxide-hydroxide/Al₂O₃m8 Thiophenol c9 Palladium/SiO₂ m9 Thioanisole c10 Palladium oxide/SiO₂m10 Sulfolane c11 mixed Palladium oxide-hydroxide/SiO₂ m11 Thiourea c12Pd/CaCO₃ m12 Na₂S₂O₃—xH₂O c13 Pd/C-diphenylsulfide m13 Na₂S c14 Pd/BaSO₄m14 Chinoline c15 Pd(II)acetate-Polymethylhydrosiloxane m15 PPh₃ c16 Pd(Fe)/C m16 Mo(CO)₆ c17 Pd/C 5% sulfur m17 V(V) oxide c18 5% Pd/0.5% Vm18 V(IV) oxide c19 Pd/Pt m19 V(III) sulfide m20 NH₄VO₃ m21 ZnBr₂ m22ZnCl₂ m23 MgBr₂ m24 MgO m25 FeCl₂ m26 FeCl₃ m27 Fe(OAc)₂) m28n-Tetramethylammonium iodide m29 n-Tetraethylammonium iodide m30n-Tetrabutylammonium iodide m31 n-Tetramethylammonium bromide (TMAB) m32n-Tetraethylammonium bromide m33 n-Tetrabutylammoniumbromide (TBAB) m34n-Tetramethylammonium chloride m35 n-Tetraethylammonium chloride m36n-Tetrabutylammoniumchloride m37 NaCl m38 NaBr m39 NaI m40 KCl m41 KBrm42 KI m43 LiBr m44 MgBr₂ m45 AlCl₃ m46 CeCl₃ m47 CuCl m48 CuBr m49 CuIm50 CuBr₂ m51 BaSO₄c1+m1+a1, c1+m2+a1, c1+m3+a1, c1+m4+a1, c1+m5+a1, c1+m6+a1, c1+m7+a1,c1+m8+a1, c1+m9+a1, c1+m10+a1, c1+m11+a1, c1+m12+a1, c1+m13+a1,c1+m14+a1, c1+m15+a1, c1+m16+a1, c1+m17+a1, c1+m18+a1, c1+m19+a1,c1+m20+a1, c1+m21+a1, c1+m22+a1, c1+m23+a1, c1+m24+a1, c1+m25+a1,c1+m26+a1, c1+m27+a1, c1+m28+a1, c1+m29+a1, c1+m30+a1, c1+m31+a1,c1+m32+a1, c1+m33+a1, c1+m34+a1, c1+m35+a1, c1+m36+a1, c1+m37+a1,c1+m38+a1, c1+m39+a1, c1+m40+a1, c1+m41+a1, c1+m42+a1, c1+m43+a1,c1+m44+a1, c1+m45+a1, c1+m46+a1, c1+m47+a1, c1+m48+a1, c1+m49+a1,c1+m50+a1, c1+m51+a1, c1+m1+a2, c1+m2+a2, c1+m3+a2, c1+m4+a2, c1+m5+a2,c1+m6+a2, c1+m7+a2, c1+m8+a2, c1+m9+a2, c1+m10+a2, c1+m11+a2, c1+m12+a2,c1+m13+a2, c1+m14+a2, c1+m15+a2, c1+m16+a2, c1+m17+a2, c1+m18+a2,c1+m19+a2, c1+m20+a2, c1+m21+a2, c1+m22+a2, c1+m23+a2, c1+m24+a2,c1+m25+a2, c1+m26+a2, c1+m27+a2, c1+m28+a2, c1+m29+a2, c1+m30+a2,c1+m31+a2, c1+m32+a2, c1+m33+a2, c1+m34+a2, c1+m35+a2, c1+m36+a2,c1+m37+a2, c1+m38+a2, c1+m39+a2, c1+m40+a2, c1+m41+a2, c1+m42+a2,c1+m43+a2, c1+m44+a2, c1+m45+a2, c1+m46+a2, c1+m47+a2, c1+m48+a2,c1+m49+a2, c1+m50+a2, c1+m51+a2, c1+m1+a3, c1+m2+a3, c1+m3+a3, c1+m4+a3,c1+m5+a3, c1+m6+a3, c1+m7+a3, c1+m8+a3, c1+m9+a3, c1+m10+a3, c1+m11+a3,c1+m12+a3, c1+m13+a3, c1+m14+a3, c1+m15+a3, c1+m16+a3, c1+m17+a3,c1+m18+a3, c1+m19+a3, c1+m20+a3, c1+m21+a3, c1+m22+a3, c1+m23+a3,c1+m24+a3, c1+m25+a3, c1+m26+a3, c1+m27+a3, c1+m28+a3, c1+m29+a3,c1+m30+a3, c1+m31+a3, c1+m32+a3, c1+m33+a3, c1+m34+a3, c1+m35+a3,c1+m36+a3, c1+m37+a3, c1+m38+a3, c1+m39+a3, c1+m40+a3, c1+m41+a3,c1+m42+a3, c1+m43+a3, c1+m44+a3, c1+m45+a3, c1+m46+a3, c1+m47+a3,c1+m48+a3, c1+m49+a3, c1+m50+a3, c1+m51+a3, c1+m1+a4, c1+m2+a4,c1+m3+a4, c1+m4+a4, c1+m5+a4, c1+m6+a4, c1+m7+a4, c1+m8+a4, c1+m9+a4,c1+m10+a4, c1+m11+a4, c1+m12+a4, c1+m13+a4, c1+m14+a4, c1+m15+a4,c1+m16+a4, c1+m17+a4, c1+m18+a4, c1+m19+a4, c1+m20+a4, c1+m21+a4,c1+m22+a4, c1+m23+a4, c1+m24+a4, c1+m25+a4, c1+m26+a4, c1+m27+a4,c1+m28+a4, c1+m29+a4, c1+m30+a4, c1+m31+a4, c1+m32+a4, c1+m33+a4,c1+m34+a4, c1+m35+a4, c1+m36+a4, c1+m37+a4, c1+m38+a4, c1+m39+a4,c1+m40+a4, c1+m41+a4, c1+m42+a4, c1+m43+a4, c1+m44+a4, c1+m45+a4,c1+m46+a4, c1+m47+a4, c1+m48+a4, c1+m49+a4, c1+m50+a4, c1+m51+a4,c2+m1+a1, c2+m2+a1, c2+m3+a1, c2+m4+a1, c2+m5+a1, c2+m6+a1, c2+m7+a1,c2+m8+a1, c2+m9+a1, c2+m10+a1, c2+m11+a1, c2+m12+a1, c2+m13+a1,c2+m14+a1, c2+m15+a1, c2+m16+a1, c2+m17+a1, c2+m18+a1, c2+m19+a1,c2+m20+a1, c2+m21+a1, c2+m22+a1, c2+m23+a1, c2+m24+a1, c2+m25+a1,c2+m26+a1, c2+m27+a1, c2+m28+a1, c2+m29+a1, c2+m30+a1, c2+m31+a1,c2+m32+a1, c2+m33+a1, c2+m34+a1, c2+m35+a1, c2+m36+a1, c2+m37+a1,c2+m38+a1, c2+m39+a1, c2+m40+a1, c2+m41+a1, c2+m42+a1, c2+m43+a1,c2+m44+a1, c2+m45+a1, c2+m46+a1, c2+m47+a1, c2+m48+a1, c2+m49+a1,c2+m50+a1, c2+m51+a1, c2+m1+a2, c2+m2+a2, c2+m3+a2, c2+m4+a2, c2+m5+a2,c2+m6+a2, c2+m7+a2, c2+m8+a2, c2+m9+a2, c2+m10+a2, c2+m11+a2, c2+m12+a2,c2+m13+a2, c2+m14+a2, c2+m15+a2, c2+m16+a2, c2+m17+a2, c2+m18+a2,c2+m19+a2, c2+m20+a2, c2+m21+a2, c2+m22+a2, c2+m23+a2, c2+m24+a2,c2+m25+a2, c2+m26+a2, c2+m27+a2, c2+m28+a2, c2+m29+a2, c2+m30+a2,c2+m31+a2, c2+m32+a2, c2+m33+a2, c2+m34+a2, c2+m35+a2, c2+m36+a2,c2+m37+a2, c2+m38+a2, c2+m39+a2, c2+m40+a2, c2+m41+a2, c2+m42+a2,c2+m43+a2, c2+m44+a2, c2+m45+a2, c2+m46+a2, c2+m47+a2, c2+m48+a2,c2+m49+a2, c2+m50+a2, c2+m51+a2, c2+m1+a3, c2+m2+a3, c2+m3+a3, c2+m4+a3,c2+m5+a3, c2+m6+a3, c2+m7+a3, c2+m8+a3, c2+m9+a3, c2+m10+a3, c2+m11+a3,c2+m12+a3, c2+m13+a3, c2+m14+a3, c2+m15+a3, c2+m16+a3, c2+m17+a3,c2+m18+a3, c2+m19+a3, c2+m20+a3, c2+m21+a3, c2+m22+a3, c2+m23+a3,c2+m24+a3, c2+m25+a3, c2+m26+a3, c2+m27+a3, c2+m28+a3, c2+m29+a3,c2+m30+a3, c2+m31+a3, c2+m32+a3, c2+m33+a3, c2+m34+a3, c2+m35+a3,c2+m36+a3, c2+m37+a3, c2+m38+a3, c2+m39+a3, c2+m40+a3, 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c18+m29+a2, c18+m30+a2, c18+m31+a2, c18+m32+a2, c18+m33+a2,c18+m34+a2, c18+m35+a2, c18+m36+a2, c18+m37+a2, c18+m38+a2, c18+m39+a2,c18+m40+a2, c18+m41+a2, c18+m42+a2, c18+m43+a2, c18+m44+a2, c18+m45+a2,c18+m46+a2, c18+m47+a2, c18+m48+a2, c18+m49+a2, c18+m50+a2, c18+m51+a2,c18+m1+a3, c18+m2+a3, c18+m3+a3, c18+m4+a3, c18+m5+a3, c18+m6+a3,c18+m7+a3, c18+m8+a3, c18+m9+a3, c18+m10+a3, c18+m11+a3, c18+m12+a3,c18+m13+a3, c18+m14+a3, c18+m15+a3, c18+m16+a3, c18+m17+a3, c18+m18+a3,c18+m19+a3, c18+m20+a3, c18+m21+a3, c18+m22+a3, c18+m23+a3, c18+m24+a3,c18+m25+a3, c18+m26+a3, c18+m27+a3, c18+m28+a3, c18+m29+a3, c18+m30+a3,c18+m31+a3, c18+m32+a3, c18+m33+a3, c18+m34+a3, c18+m35+a3, c18+m36+a3,c18+m37+a3, c18+m38+a3, c18+m39+a3, c18+m40+a3, c18+m41+a3, c18+m42+a3,c18+m43+a3, c18+m44+a3, c18+m45+a3, c18+m46+a3, c18+m47+a3, c18+m48+a3,c18+m49+a3, c18+m50+a3, c18+m51+a3, c18+m1+a4, c18+m2+a4, c18+m3+a4,c18+m4+a4, c18+m5+a4, c18+m6+a4, c18+m7+a4, c18+m8+a4, c18+m9+a4,c18+m10+a4, c18+m11+a4, c18+m12+a4, c18+m13+a4, c18+m14+a4, c18+m15+a4,c18+m16+a4, c18+m17+a4, c18+m18+a4, c18+m19+a4, c18+m20+a4, c18+m21+a4,c18+m22+a4, c18+m23+a4, c18+m24+a4, c18+m25+a4, c18+m26+a4, c18+m27+a4,c18+m28+a4, c18+m29+a4, c18+m30+a4, c18+m31+a4, c18+m32+a4, c18+m33+a4,c18+m34+a4, c18+m35+a4, c18+m36+a4, c18+m37+a4, c18+m38+a4, c18+m39+a4,c18+m40+a4, c18+m41+a4, c18+m42+a4, c18+m43+a4, c18+m44+a4, c18+m45+a4,c18+m46+a4, c18+m47+a4, c18+m48+a4, c18+m49+a4, c18+m50+a4, c18+m51+a4,c19+m1+a1, c19+m2+a1, c19+m3+a1, c19+m4+a1, c19+m5+a1, c19+m6+a1,c19+m7+a1, c19+m8+a1, c19+m9+a1, c19+m10+a1, c19+m11+a1, c19+m12+a1,c19+m13+a1, c19+m14+a1, c19+m15+a1, c19+m16+a1, c19+m17+a1, c19+m18+a1,c19+m19+a1, c19+m20+a1, c19+m21+a1, c19+m22+a1, c19+m23+a1, c19+m24+a1,c19+m25+a1, c19+m26+a1, c19+m27+a1, c19+m28+a1, c19+m29+a1, c19+m30+a1,c19+m31+a1, c19+m32+a1, c19+m33+a1, c19+m34+a1, c19+m35+a1, c19+m36+a1,c19+m37+a1, c19+m38+a1, c19+m39+a1, c19+m40+a1, c19+m41+a1, c19+m42+a1,c19+m43+a1, c19+m44+a1, c19+m45+a1, c19+m46+a1, c19+m47+a1, c19+m48+a1,c19+m49+a1, c19+m50+a1, c19+m51+a1, c19+m1+a2, c19+m2+a2, c19+m3+a2,c19+m4+a2, c19+m5+a2, c19+m6+a2, c19+m7+a2, c19+m8+a2, c19+m9+a2,c19+m10+a2, c19+m11+a2, c19+m12+a2, c19+m13+a2, c19+m14+a2, c19+m15+a2,c19+m16+a2, c19+m17+a2, c19+m18+a2, c19+m19+a2, c19+m20+a2, c19+m21+a2,c19+m22+a2, c19+m23+a2, c19+m24+a2, c19+m25+a2, c19+m26+a2, c19+m27+a2,c19+m28+a2, c19+m29+a2, c19+m30+a2, c19+m31+a2, c19+m32+a2, c19+m33+a2,c19+m34+a2, c19+m35+a2, c19+m36+a2, c19+m37+a2, c19+m38+a2, c19+m39+a2,c19+m40+a2, c19+m41+a2, c19+m42+a2, c19+m43+a2, c19+m44+a2, c19+m45+a2,c19+m46+a2, c19+m47+a2, c19+m48+a2, c19+m49+a2, c19+m50+a2, c19+m51+a2,c19+m1+a3, c19+m2+a3, c19+m3+a3, c19+m4+a3, c19+m5+a3, c19+m6+a3,c19+m7+a3, c19+m8+a3, c19+m9+a3, c19+m10+a3, c19+m11+a3, c19+m12+a3,c19+m13+a3, c19+m14+a3, c19+m15+a3, c19+m16+a3, c19+m17+a3, c19+m18+a3,c19+m19+a3, c19+m20+a3, c19+m21+a3, c19+m22+a3, c19+m23+a3, c19+m24+a3,c19+m25+a3, c19+m26+a3, c19+m27+a3, c19+m28+a3, c19+m29+a3, c19+m30+a3,c19+m31+a3, c19+m32+a3, c19+m33+a3, c19+m34+a3, c19+m35+a3, c19+m36+a3,c19+m37+a3, c19+m38+a3, c19+m39+a3, c19+m40+a3, c19+m41+a3, c19+m42+a3,c19+m43+a3, c19+m44+a3, c19+m45+a3, c19+m46+a3, c19+m47+a3, c19+m48+a3,c19+m49+a3, c19+m50+a3, c19+m51+a3, c19+m1+a4, c19+m2+a4, c19+m3+a4,c19+m4+a4, c19+m5+a4, c19+m6+a4, c19+m7+a4, c19+m8+a4, c19+m9+a4,c19+m10+a4, c19+m11+a4, c19+m12+a4, c19+m13+a4, c19+m14+a4, c19+m15+a4,c19+m16+a4, c19+m17+a4, c19+m18+a4, c19+m19+a4, c19+m20+a4, c19+m21+a4,c19+m22+a4, c19+m23+a4, c19+m24+a4, c19+m25+a4, c19+m26+a4, c19+m27+a4,c19+m28+a4, c19+m29+a4, c19+m30+a4, c19+m31+a4, c19+m32+a4, c19+m33+a4,c19+m34+a4, c19+m35+a4, c19+m36+a4, c19+m37+a4, c19+m38+a4, c19+m39+a4,c19+m40+a4, c19+m41+a4, c19+m42+a4, c19+m43+a4, c19+m44+a4, c19+m45+a4,c19+m46+a4, c19+m47+a4, c19+m48+a4, c19+m49+a4, c19+m50+a4, c19+m51+a4.

Pressure

The catalytic hydrogenation according to the invention is preferablyperformed under elevated pressure (i.e. up to about 600 bar), preferablyin an autoclave in a hydrogen gas atmosphere, preferably in a semi batchhydrogenation process. The (additional) pressure increase can be broughtabout by supply of an inert gas, such as nitrogen or argon. Thehydrogenation according to the invention is effected preferably at ahydrogen pressure in the range from about 0 to about 300 bar, morepreferably at a hydrogen pressure in the range from about 5 to about 200bar. Preferred ranges of hydrogen pressure are also e from about 0.5 toabout 150 bar.

In one embodiment the catalytic hydrogenation according to the inventionis preferably performed under elevated pressure (i.e. up to about 200bar).

The hydrogen pressure according to the invention can also vary duringthe process.

If necessary, suitable measures for dissipating heat from the exothermicreaction can be applied.

Temperature

The catalytic hydrogenation according to the invention is performedpreferably at a temperature in the range from about −20° C. to about200° C., more preferably at a temperature in the range from about 0° C.to about 100° C., most preferably in the range from about 5 to 70° C.

Solvents

The catalytic hydrogenation can also be performed without a solvent.However, it is generally advantageous to perform the process accordingto the invention in the presence of solvents (diluents). Solvents areadvantageously used in such an amount that the reaction mixture remainsefficiently stirrable over the entire process. Advantageously, based onthe nitrile used, 1 to 50 times the amount of solvent, preferably 2 to40 times the amount of solvent and more preferably 2 to 30 times theamount of solvent is used.

Useful solvents for the performance of the hydrogenation processaccording to the invention include water and all organic solvents whichare inert under the reaction conditions, the type of solvent useddepending on the type of reaction procedure, more particularly on thetype of catalyst used and/or the hydrogen source (introduction ofgaseous hydrogen or generation in situ). Solvents are also understood inaccordance with the invention to mean mixtures of pure solvents.

Solvents suitable in accordance to the invention are water, acids suchas acetic acid, acetic anhydride, alcohols such as methanol, ethanol,isopropanol, butanol, t-amyl alcohol, benzyl alcohol, 1,3-butanediol,1,4-butandiol, 2-butoxyethanol, cyclohexanol, diethylene glycol,diethylen glycol methyl ether, dipropylene glycol, dipropylene glycolmethyl ether, 2-ethoxyethanol, ethanolamine, ethylene glycol, glycerol,hexanole, hexylene glycol, isoamyl alcohol, isobutanol,2-methoxyethanol, 1-octanol, pentanol, propylene glycol, tetraethyleneglycol, triethylene glycol; ethers, such as ethyl propyl ether, methyltert-butyl ether, n-butyl ether, anisole, phenetole, cyclohexyl methylether, dimethyl ether, diethyl ether, dimethylglycol, diphenyl ether,dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether,diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether,tetrahydrofuran, methyl tetrahydrofuran, methyl cyclopenthylether,dioxane, dichlorodiethyl ether, petroleum ether, ligroin and polyethersof ethylene oxide and/or propylene oxide; ketones such as acetone,cyclohexanone, 3-pentanone, amines, such as trimethyl-, triethyl-,tripropyl-, and tributylamine, tert-amyl methyl ether (TAME), N-methylmorpholine, aliphatic, cycloaliphatic or aromatic hydrocarbons such aspentane, hexane, methyl cyclohexane heptane, octane, nonane, andtechnical-grade hydrocarbons which may be substituted by fluorine andchlorine atoms, such as dichloromethane, fluorobenzene, chlorobenzene ordichlorobenzene, for example white spirits having components withboiling points in the range, for example, from 40° C. to 250° C.,cymene, petroleum fractions within a boiling range from 70° C. to 190°C., toluene, xylenes, ethylbenzene. esters such as amyl acetates, butylacetates, ethyl acetate, isobutyl acetate, isopropyl acetate,2-methoxyethyl acetate, methyl acetate, propyl acetate, prop glycolmethyl ether acetate, carbonate such as propylene carbonate, dimethylcarbonate, diethyl carbonate; N,N-Dimethylacetimide,N,N-Dimethylformamide, 2-pyrrolidone and N-methyl pyrrolidone.

In the process according to the invention, it is preferred to usealcohols or cyclic ethers as solvent. Preferred is methanol, ethanol,isopropanol, t-butanol, tetrahydrofuran, or methyltetrahydrofuran. Amongbefore mentioned solvents methanol is preferred. It is further preferredthat from the group of suitable solvents to be used in the hydrogenationreaction acids such as acetic acid and acetic anhydride are excluded.

The solvents, which may be used in the additional process stepsfollowing the hydrogenation step (A1) may be independently selected fromthe solvents as defined above for the hydrogenation step (A1).

The solvents which can be used in step (A1), (A3) and (A5) can be thesame or different and can independently in each case be used as mixturesof solvents, in particular mixtures comprising water or as solventsconsisting of only one component.

Route B

Another aspect the present invention describes a process (B) for theproduction of a compound according to formula (I)

wherein p and X are defined as above;

q is an integer equal to 1, 2, 3 or 4;

each substituent Y is chosen, independently of the others, as beinghalogen, C₁-C₄ alkyl or C₁-C₄ haloalkyl;

wherein in the first step (B1)

a substituted 2-methyl cyanopyridyl derivative according to formula (II)

wherein p and X are defined as above;

is hydrogenated in the presence of a metal catalyst, an catalystmodifier, and an acid to

a substituted 2-ethylaminopyridine derivative according to the formula(III) or corresponding salts thereof,

wherein X, p are defined as above;

where in the second step (B2) a substituted 2-ethylaminopyridinederivative according to the formula (III) as defined in step (B1) isreacted with a benzoyl halide according to formula (IV)

wherein

Hal is fluorine, chlorine or bromine;

q is an integer equal to 1, 2, 3 or 4;

each substituent Y is chosen, independently of the others, as beinghalogen, C₁-C₄ alkyl or C₁-C₄ haloalkyl;

to the compound according to formula (I).

Preferably the compound according to formula (I) is Fluopyram(N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl)benzamide,the compound according to formula (Ia).

Optionally in the third step (B3) a solvent and an acid are added to thereaction mixture comprising the precipitated compound according toformula (I).

Optionally in the third step (B3) the aequous phase can be removed fromthe reaction mixture.

Optionally in the fourth step (B4) the organic phase comprising thecompound according to formula (I) is separated from the phase comprisingwater.

q is preferably 1 or 2.

q is very preferably 1.

In each case, Y is preferably independently of the others, as beingfluorine, chlorine, bromine, C₁-C₂ alkyl or C₁-C₂ haloalkyl having 1 to5 halogen atoms selected independently from each other from fluorine,chlorine;

In each case, Y is more preferably independently of the others, as beingfluorine, chlorine, methyl, ethyl or C₁-C₂ haloalkyl having 1 to 5halogen atoms selected independently from each other from fluorine,chlorine;

In each case, Y is particular preferably independently of the others, asbeing fluorine, chlorine, or difluoromethyl, trifluoromethyl,dichloromethyl, trichloromethyl;

In each case, Y is very particular preferably trifluoromethyl.

In each case, Y is very particular preferably chlorine.

As regards the positions in which the phenyl moiety is substituted by Y,the phenyl moiety is preferably substituted by Y in 2- and/or in6-position. Preferably, the phenyl moiety is substituted by Y in2-position.

Very particular preferably the compound according to formula (II) is3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile and the compoundaccording to formula (III) is2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine. Very preferablythe compound according to formula (IV) is 2-trifluoromethyl-benzoylchloride.

Very preferably the compound according to formula (I) is fluopyram asdefined in formula (Ia).

The corresponding salts of the compounds according to formula (III) arepreferably hydrogensulfates, sulfates, hydrochlorides, phosphates,formiates, or acetates.

Regarding the metal catalyst, the catalyst modifier and the acid used instep (B1), reference is made to the definitions and amounts as providedabove for step (A1).

Preferably step (B2) is performed in the presence of a base.

Useful bases used in step (B2) are inorganic and/or organic bases suchas Na₂CO₃, NaHCO₃, K₂CO₃, KHCO₃, NaOH, KOH, Ca(OH)₂, Mg(OH)₂, triethylamine, N,N-diisopropylethylamine.

The following bases are particularly preferred for step (B2): Na₂CO₃,NaHCO₃, K₂CO₃, KHCO₃, NaOH, KOH, Ca(OH)₂. More preferred are NaOH, KOH,Ca(OH)₂. Mostly preferred are NaOH, KOH. Preferably, in step (B2) a baseas defined herein is added until adjustment of the pH value of thereaction solution to pH 4 to 14, preferably pH 6 bis 13 is achieved.

The following bases are particularly preferred for step (B2): Na₂CO₃,NaHCO₃, K₂CO₃, KHCO₃, NaOH, KOH, Ca(OH)₂. More preferred are NaOH, KOH,Ca(OH)₂. Mostly preferred are NaOH, KOH. Preferably, in step (B2) a baseas defined herein is added until adjustment of the pH value of thereaction solution to pH 4 to 14, preferably pH 6 bis 13 is achieved.

The acid, which may be used in the additional steps following thehydrogenation reaction of step (B1), particularly in step (B3), as wellas the amount of acid used therein is defined as above for process step(A4).

The solvent as well as the amount of solvent used in steps (B1), (B2),and (B3) is defined as above for process (A).

The hydrogen pressure used in step (B1) is defined as above for process(A).

Temperature

The process step (B1) according to the invention is performed preferablyat a temperature in the range from about −20° C. to about 250° C., morepreferably at a temperature in the range from about 0° C. to about 175°C., most preferably in the range from about 0 to 150° C.

The process (B2) according to the invention is performed preferably at atemperature in the range from about −20° C. to about 250° C., morepreferably at a temperature in the range from about 0° C. to about 175°C., most preferably in the range from about 0 to 150° C.

The process (B3) according to the invention is performed preferably at atemperature in the range from about −20° C. to about 250° C., morepreferably at a temperature in the range from about 0° C. to about 175°C., most preferably in the range from about 0 to 150° C.

The process (B4) according to the invention is performed preferably at atemperature in the range from about −20° C. to about 250° C., morepreferably at a temperature in the range from about 0° C. to about 175°C., most preferably in the range from about 0 to 150° C.

EXAMPLES

The examples shown below further illustrate the invention withoutlimiting it.

Examples Regarding Process (A) Example 1: Hydrogenation with DifferentCatalyst, Different Modifiers and Sulfuric Acid

An autoclave is charged with a solution of[3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile [Py-CN], amodifier at a concentration between 0.0001 to 0.1 equivalents related tothe amount of [PyCN] and an acid in a solvent, followed by the additionof the catalyst. The catalyst, modifier, acid, and solvent can be chosenfrom the tables 1a, 1b, 1c and 1d below.

The contents are then stirred at an elevated hydrogen pressure of morethan 5 bar at 20° C. for 4 h—hydrogen uptake ceased after 3 hours andstirring is continued for another hour. The reaction mixture is removedby filtration from the autoclave. In case of recyclization the abovedescribed procedure is repeated under the same conditions as describedabove. The removed reaction mixture is analyzed by HPLC to quantify thecontent of amine.

TABLE 1a Catalysts The catalysts are commercially available catalystsfrom companies (e.g. BASF, Acros, Evonik). Ref. Catalyst c1 Pd c2 Pd/Cc3 Pd(OH)₂/C c4 Pd/Al₂O₃ c5 Palladium oxide/C c6 mixed Palladiumoxide-hydroxide/C c7 Palladium oxide/Al₂O₃ c8 mixed Palladiumoxide-hydroxide/Al₂O₃ c9 Palladium/SiO₂ c10 Palladium oxide/SiO₂ c11mixed Palladium oxide-hydroxide/SiO₂ c12 Pd/CaCO₃ c13Pd/C-diphenylsulfide c14 Pd/BaSO₄ c15Pd(II)acetate-Polymethylhydrosiloxane c16 Pd (Fe)/C c17 Pd/C 5% sulfurc18 5% Pd/0.5% V c19 Pd/Pt

TABLE 1b Modifier Ref. Modifier m1 Thiophene m2 Tetrahydrothiophene m32-Mercaptophenol m4 Cysteine m5 3,6-Dithia 1,8 octadiol m62,2′-Thiobisethanol m7 Diphenyl sulfide m8 Thiophenol m9 Thioanisole m10Sulfolane m11 Thiourea m12 Na₂S₂O₃—xH₂O m13 Na₂S m14 Chinoline m15 PPh₃m16 Mo(CO)₆ m17 V(V) oxide m18 V(IV) oxide m19 V(III) sulfide m20 NH₄VO₃m21 ZnBr₂ m22 ZnCl₂ m23 MgBr₂ m24 MgO m25 FeCl₂ m26 FeCl₃ m27 Fe(OAc)₂)m28 n-Tetramethylammonium iodide m29 n-Tetraethylammonium iodide m30n-Tetrabutylammonium iodide m31 n-Tetramethylammonium bromide (TMAB) m32n-Tetraethylammonium bromide m33 n-Tetrabutylammoniumbromide (TBAB) m34n-Tetramethylammonium chloride m35 n-Tetraethylammonium chloride m36n-Tetrabutylammoniumchloride m37 NaCl m38 NaBr m39 NaI m40 KCl m41 KBrm42 KI m43 LiBr m44 MgBr₂ m45 AlCl₃ m46 CeCl₃ m47 CuCl m48 CuBr m49 CuIm50 CuBr₂ m51 BaSO₄

TABLE 1c Acid Ref. Acid a1 Sulfuric acid a2 HCl a3 Phosphoric acid a4Methanesulfonic acid

TABLE 1d Solvent Ref. Solvent s1 Methanol s2 Ethanol s3 isopropanol s4t-butanol s5 tetrahydrofuran s6 methyltetrahydrofuran

From the tables 1a, 1b, 1c and 1d any combination of catalyst, modifier,acid and solvent c1m1a1s1 to c19m51a4s6 can be selected.

Example 2: Hydrogenation with Different Catalysts, Different Modifiersand Sulfuric Acid

An autoclave was charged with a solution of[3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile [Py-CN], modifieras listed in table 2a and 2b below at a concentration between 0.0001 to0.1 equivalents related to the amount of [PyCN] and sulfuric acid inmethanol, followed by the addition of the catalyst as listed in table 2aand 2b below. The catalysts are commercially available catalysts fromcompanies (e.g. BASF, Acros, Evonik). The contents were then stirred atan elevated hydrogen pressure of more than 5 bar at 20° C. for 4h—hydrogen uptake ceased after 3 hours and stirring was continued foranother hour. The reaction mixture was removed by filtration from theautoclave. In case of recyclization the above described procedure wasrepeated under the same conditions as described above. The removedreaction mixture was analyzed by HPLC to quantify the content of amine.The HPLC yield of 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamineis shown in table 2a and 2b below.

TABLE 2a Catalyst Modifier yield Deschloro HPLC Entry [mol %] [mol %][%] [area-%]  1 5% Pd/C KBr 83.7  2 5% Pd/C Fe(OAc)₂ 50.6 38.22  3 5%Pd/C BaSO₄ 52.1 38.45  4 5% Pd + 0.5% V NaBr 75.3 3.45 2 mol % 3.3 mol % 5 4% Pd 1% Pt TBAB 51.1 10.10 2 mol % 3.3 mol %  6a 10% Pd/C NaBr 86.77.33  6b 10% Pd/C TBAB 84.4 10.50  7 10% Pd/C KBr 78.6  8a 10% Pd/CNa₂S₂O₃—xH₂O 49.7 5.56 2 mol % 0.5 mol %  8b 10% Pd/C TBAB 85.8 10.7 3mol % 5 mol %  9 10% Pd/C PPh₃ 0.4 0 2 mol % 3 mol % 10 20% Pd(OH)₂/CBa₂SO₄ 59.6 33.68 2 mol % 11 20% Pd NaBr 88.3 4.15 (Cat No 1) 3 mol % 2mol % 12 20% Pd TBAB 89.2 4.43 (Cat No 1) 3 mol % 2 mol % 13 20% PdZnBr₂ 76.7 4.57 (Cat No 1) 3 mol % 2 mol % 14 20% Pd Cysteine 49.7 7.86(Cat No 1) 0.5 mol % 2 mol % 15 20% Pd TBAB 90.9 4.89 (Cat No 2) 5 mol %3 mol % 16 20% Pd TBAB 91.1 4.96 (Cat No 3) 5 mol % 3 mol % 17 20% PdTBAB 91.0 5.40 (Cat No 4) 5 mol % 3 mol % 18 20% Pd TBAB 90.3 5.16 (CatNo 5) 5 mol % 3 mol % 19 20% Pd TBAB 90.1 5.27 (Cat No 6) 5 mol % 3 mol% 20 Rh/C TBAB 16.25 0 3.3 mol % 21 Pt/C TBAB 4.30 0.21 3.3 mol %

Comparative Example

TABLE 2b Catalyst Modifier yield Deschloro HPLC Entry [mol %] [mol %][%] [area-%] 22 5% Pd + 0.5% V without 62.9 19.17 2 mol % modifier

Example 3: Hydrogenation with Palladium Catalyst, Different Modifiersand Sulfuric Acid

An autoclave was charged with a solution of[3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile [Py-CN], amodifier as listed below in table 3 and sulfuric acid in methanol,followed by the addition of Pd(OH)₂/on carbon. The contents were thenstirred at an elevated hydrogen pressure of more than 5 bar at 20° C.for 1-4 h—hydrogen uptake ceased after 1-3 hours and stirring wascontinued for another hour. The reaction mixture was removed byfiltration from the autoclave. The removed reaction mixture was analyzedby HPLC to quantify the content of amine. After filtration of thecatalyst the methanolic solution is evaporated in vacuo. The residue wasre-dissolved in water and evaporated again to remove remaining methanol.The mixture is cooled down to 10° C. followed by addition of a base toadjust the pH to 7-14. Then solvent (e. g. toluene, xylene,methylcyclohexane, tetrahydrofurane, methyltertbutylether) can be addedto the solution and the organic phase is separated. The water phase isextracted again with a suitable solvent. To this mixture an acid (e.g.hydrochloric acid (gaseous or aequous) can be added slowly, optionallyfollowed by a distillation step. The amine salt e.g. amine hydrochlorideprecipitated out. Then a defined amount of water and organic solvent, ifnecessary, can be added to the solution. The solid was filtrated, washedwith e.g. toluene and dried under reduced pressure.

The results are shown in table 3a and 3b below for the differentmodifiers.

TABLE 3a yield Deschloro HPLC Entry Modifier [%] [area-%] 1 V(V)oxid 5mol % 56.5 31.79 2 V(IV)oxid 5 mol % 60.3 30.33 3 V(III)sulfide (0.1 mol%) 54.9 37.5 4 V(III)sulfide (5 mol %) 0.9 0.09 5 MgO 5 mol % 42.6 7.216 ZnBr₂ 5 mol % 76.1 1.67 7 NH₄VO₃ 5 mol % 64.6 24.7 8 1 mol % CuI 7.80.05 8 5 mol % FeCl₃ 70.6 13.36 9 5 mol % Fe(OAc)₂ 61.7 27.25 10 1 mol %NaI 1.4 0 11 1 mol % KI 0.3 0 12 TMAB 86.1 6.08 13 TBAB 91 5 14 4 mol %Thiourea 0.1 0 15 1800 ppm 3,6-dithia-1,8-octadiole 60.3 8.1 16Tetrahydrothiophene >70 17 PPh₃ 0.20 mol % 81 8.08 18 NaBr 91.34 4.06 19KBr 2 mol % 86.8 8.61 20 2-Mercaptophenol 49.8 21 2-Mercaptophenol 1.57mg 41.5 21 Chinolin 5 mol % 57.4 10.14 22 Mo(CO)6 0.002 mol % 33.5 4.86

Comparative Example

To show the effect of the specific combination of the present invention,a hydrogenation reaction was carried out as described in Example 3,wherein the [3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile[Py-CN] was hydrogenated

-   -   a) without adding an acid and without adding a modifier (Table        3b, Entry 1),    -   b) in the presence of an acid without adding a modifier (Table        3b, Entry 2),    -   c) in the presence of a catalyst modifier without adding an acid        (Table 3b, Entry 3), and    -   d) in the presence of a modifier and an acid, according to the        present invention, (Table 3b, Entry 4).

The results are shown in table 3b:

TABLE 3b Catalyst Modifier Acid yield Deschloro HPLC Entry [mol %] [mol%] [mol %] [%] [area-%] 1 Pd(OH)₂/C — — 14.78 8.20 2 2 Pd(OH)₂/C — H₂SO₄62.9 28.6 2 120 3 Pd(OH)₂/C TBAB — 13.26 3.84 2 3.3 4 Pd(OH)₂/C TBABH₂SO₄ 91.0 5.0 2 3.3 120

The Comparative Example clearly shows that only the specific combinationof the present invention, comprising a palladium catalyst, a catalystmodifier and an acid, achieves improved yields and reduced contents ofthe dechlorinated side product2-[5-(trifluoromethyl)pyridin-2-yl]ethanamine.

Example 4: Hydrogenation with the Catalyst Pd(OH)2/C, Different Solventsand Sulfuric Acid

An autoclave was charged with a solution of[3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile [Py-CN], TBAB orTMAB at a concentration between 1 to 5 w/w % related to the amount of[Py-CN] and the solvent as listed below, followed by the addition ofPd(OH)₂ on carbon. The contents were then stirred at an elevatedhydrogen pressure of more than 5 bar at 20° C. for 4 h—hydrogen uptakeceased after 3 hours and stirring was continued for another hour. Thereaction mixture was removed by filtration from the autoclave. Theremoved reaction mixture was analyzed by HPLC to quantify the content ofamine. The HPLC yield of2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamine is shown in table4 below.

TABLE 4 HPLC-yield Solvent [%] AcOH/water >70% Ethanol >60%Methanol >70% Tetrahydrofuran >40%

Example 5: Hydrogenation with the Catalyst Pd(OH)_(2/)C or Pd/C, in MeOHand Different Acids

An autoclave was charged with a solution of[3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetonitrile [Py-CN], TBAB orTMAB at a concentration between 1 to 5 w/w % related to the amount of[Py-CN] and an acid as listed below in methanol, followed by theaddition of Pd(OH)₂ on carbon or Pd/C. The contents were then stirred atan elevated hydrogen pressure of more than 5 bar at 20° C. for 4h—hydrogen uptake ceased after 3 hours and stirring was continued foranother hour. The reaction mixture was removed by filtration from theautoclave. In case of recyclization the above described procedure wasrepeated under the same conditions as described above. The removedreaction mixture was analyzed by HPLC to quantify the content of amine.The HPLC yield of 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanamineis shown in table 5 below.

TABLE 5 HPLC-yield Acid [%] HCl >70% Acetic acid >20% Methanesulfonicacid >40%

Example Regarding Process (B) Example 6

Step B1 was performed according to the examples given in examples 1 to5.

After filtration of the catalyst the methanolic solution was evaporatedin vacuo. The residue was re-dissolved in water and evaporated again toremove remaining methanol. The solution was cooled down. The acidechloride i.e. 2-trifluoromethyl benzoyl chloride, was added at pH 7 to8. After complete addition of the benzoyl chloride the suspension wasstirred for additional 1 h at 20° C. before the addition of solvent(e.g. toluene, xylene, methylcyclohexane, tetrahydrofurane,methyltertbutylether, water). The mixture was heated up to over 85° C.The water phase was then separated and an acid (e.g. aqueous HCl,sulfuric acid, acetic acid) was added to the mixture and stirred foradditional 15 minutes. The product precipitates. The cake was washedfirst with water and then with a solvent before drying under vacuo.

What is claimed is:
 1. A process (B) for production of a compoundaccording to formula (I)

wherein p is an integer equal to 1, 2, 3 or 4; each substituent X ischosen, independently of the others, as being halogen, C₁-C₄ alkyl C₁-C₄haloalkyl; q is an integer equal to 1, 2, 3 or 4; each substituent Y ischosen, independently of the others, as being halogen, C₁-C₄ alkyl orC₁-C₄ haloalkyl; comprising in (B1) hydrogenating a substituted 2-methylcyanopyridyl derivative according to formula (II)

in the presence of a metal catalyst, an catalyst modifier, and an acidto a substituted 2-ethylaminopyridine derivative according to formula(III) or a corresponding salt thereof,

and in (B2) reacting a substituted 2-ethylaminopyridine derivativeaccording to the formula (III) as defined in (B1), with a benzoyl halideaccording to formula (IV)

wherein Hal is fluorine, chlorine or bromine; q is an integer equal to1, 2, 3 or 4; each substituent Y is chosen, independently of the others,as being halogen, C₁-C₄ alkyl or C₁-C₄ haloalkyl; to a compoundaccording to formula (I).
 2. A process according to claim 1, furthercomprising in (B3), adding a solvent and an acid to a reaction mixturecomprising a precipitated compound according to formula (I).
 3. Aprocess according to claim 2 comprising in (B4), separating an organicphase comprising a compound according to formula (I) from a water phase.4. A process according to claim 3, comprising in (B2), adding a base toa reaction mixture.
 5. A process according to claim 1 wherein p is 1 or2; q is 1; Y is independently of the others, as being fluorine,chlorine, or difluoromethyl, trifluoromethyl, dichloromethyl,trichloromethyl; and the phenyl moiety is substituted by Y in 2- and/orin 6-position; X is independently of the others, as being fluorine,chlorine, or difluoromethyl, trifluoromethyl, dichloromethyl,trichloromethyl; and the 2-pyridyl moiety is substituted by X in 3-and/or in 5-position.
 6. A process according to claim 1, wherein thecompound according to formula (I) is(N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl)benzamide).